M1 - Antidepressants

Question 1

What is the mechanism of Desvenlafaxine?

Answer 1

SNRI that primarily affects serotonin transporters ( 5HTT) more than norepinephrine transporters (NAT).

Question 2

What are the actions of Trazodone extended release? (2)

Answer 2

1. SSRI
2. 5HT2A/5HT2C antagonist, useful for sleep disturbances and depression.

Question 3

What makes Vilazodone unique among antidepressants? (2)

Answer 3

1. SSRI
2. Partial agonist at 5HT1A receptors (SPARI: Serotonin Partial Agonist Reuptake Inhibitor).

Question 4

What are the receptor actions of Vortioxetine? (4)

Answer 4

1. SSRI
2. Agonist at 5HT1A
3. Antagonist at 5HT3 and 5HT7.
4. Partial agonist at 5HT1B.

Question 5

What is the mechanism of action of Dextromethorphan-Bupropion? (2)

Answer 5

1. Norepinephrine-Dopamine Reuptake Inhibitor.
2. NMDA receptor antagonist.

Question 6

Why are ketamine and esketamine used for depression?

Answer 6

They are NMDA receptor antagonists, offering rapid relief for treatment-resistant depression.

Question 7

What is the monoamine hypothesis of depression?

Answer 7

Suggests that decreased levels of monoamine neurotransmitters (5HT, NA, DA) contribute to Major Depressive Disorder (MDD).

Question 8

What role does the kappa opioid receptor play in depression?

Answer 8

Activation by dynorphin inhibits dopamine neurons in the VTA, contributing to anhedonia and depressive symptoms.

Question 9

How do kappa opioid receptor antagonists work in depression? (2)

Answer 9

1. Block dynorphin’s effects on kappa receptors.
2. Prevent anhedonia and show antidepressant effects in preclinical studies.

Question 10

What is the message-address concept in drug design? (2)

Answer 10

1. Message Component: Determines receptor recognition.
2. Address Component: Confers selectivity for specific receptor subtypes.

Question 11

Name some kappa opioid antagonists. (3)

Answer 11

1. norBNI: Potent kappa antagonist.
2. GNTI: Highly selective for kappa receptors.
3. JDTic: Potent and selective kappa antagonist.

Question 12

What are some limitations of current antidepressant research? (3)

Answer 12

1. Limited understanding of neurobiology.
2. Heterogeneity of depression.
3. Reliance on animal models with limited predictive power for human responses.

Question 13

Why is the regulatory environment challenging for novel antidepressants? (2)

Answer 13

1. Difficulty in getting approval for studying new targets like psychedelics.
2. Lack of diagnostic tools for personalized treatment.

Question 14

How does CREB contribute to depression via kappa opioid receptors? (2)

Answer 14

1. CREB activation increases dynorphin levels.
2. Dynorphin inhibits VTA dopamine neurons, causing anhedonia.

Question 15

What is the significance of the phenylpiperidine motif in drug development?

Answer 15

It’s used to design selective opioid antagonists with improved potency and pharmacokinetics.

Question 16

What was Alkermes’ approach in developing antidepressants?

Answer 16

Combined buprenorphine (mu partial agonist/kappa antagonist) with a mu antagonist to treat treatment-resistant depression.

Question 17

What are the benefits of JDTic as a kappa antagonist? (2)

Answer 17

1. Highly potent and selective.
2. Developed using the message-address concept.

Question 18

What is the rationale behind using animal models in antidepressant research?

Answer 18

To test behavioural and physiological changes, such as anhedonia and despair, relevant to depressive symptoms.

Question 19

What are emerging targets in antidepressant research beyond monoamines? (3)

Answer 19

1. Kappa opioid receptors
2. NMDA receptors
3. Neuroinflammatory pathways.

Question 20

What is the main limitation of preclinical antidepressant assays?

Answer 20

They often rely on current drug mechanisms, which may miss novel agents targeting alternative pathways